While most women are overweight or obese when they reach menopause, we know little about how obesity affects this transition and its impact on metabolic health. We have hypothesized that the enhanced production of estrogens in peripheral tissues of obese women protects adipose tissue, skeletal muscle, and bone from the menopause-related decline in function. We have merged well-characterized preclinical models of obesity (obesity-resistant/prone rats) and menopause surgical ovariectomy (OVX) to study how pre-existing obesity affects this transition. In the first aim, we examine obesity's effects on the loss of ovarian estrogen production and its impact on energy balance, fuel utilization, and metabolic health. The role of extragonadal estrogen production in obesity's effects will be dissected with the use of aromatase inhibitors. Diet-induced weight loss is common in women with weight control problems, but the body compensates with homeostatic adaptations that drive weight regain. The loss of ovarian function in weight reduced women may exacerbate this metabolic drive to gain weight and create a potentiated vulnerability to metabolic disease. Regular exercise and estrogen have many overlapping effects on energy balance and fuel utilization that may counter these consequences to energy homeostasis and disease. In the second aim, we examine how energy restricted weight loss from obesity affects the drive to gain weight and the decline in metabolic health after the loss of ovarian function. The impact of regular exercise, with actions that reflect an estrogen mimetic, will be examined in weight reduced subjects. These studies will provide insight into how one of the most common preconditions of menopause, obesity, affects the loss of ovarian function and its consequences to energy homeostasis and metabolic disease. Observations from these studies may provide evidence that certain populations of obese woman (treated with aromatase therapy, energy restricted) who may be particularly vulnerable to menopausal weight gain and metabolic disease unless they maintain a program of regular physical activity. RELEVANCE (See instructions): Over 60% of US women experience weight control problems prior to menopause, and menopause leads to additional weight gain. The studies in this proposal will help us understand how obesity affects menopausal weight gain and its impact on metabolic health. Our observations will further our understanding of the consequences of menopause and identify populations that are particularly vulnerable to metabolic disease.